Antiinfectives constitute a 25 billion dollar industry. Macrolides constitute one of the largest groups of antiinfectives and the erythronolide/ketolides are the single largest group among these. Such antiinfectives are the treatment of choice for respiratory tract infections, the eighth leading killer in the US.
Macrolides have a broad range of medicinal properties, especially as antiinfectives and antitumor agents. The potent and broad spectrum antibiotic erythromycin and the close relatives known as the ketolides are examples of complex macrolides. Unfortunately, many macrolides are so structurally complex that they can not be synthesized readily by known chemical methods. Instead, they are prepared semi-synthetically, i.e. fermentation processes are used to produce erythromycin and then chemical synthesis protocols that use erythromycin as a starting point are applied to produce new drug candidates. Importantly, such semi-synthetic routes—which all current routes to such candidates use—are severely limited with regard to the structural scope of macrolides that can be evaluated.
Model studies to investigate the possible use of cyclic bis-allenes as intermediates for preparing biologically active macrolides have been carried out. See Partha Ghosh (“New methods and strategies towards total synthesis of 9-S-dihydroerythronolide A,” Rutgers University, Dissertation, 2008). However, it has subsequently been determined that the conversion of compound 6.1 to compound 6.28 proposed on page 66 therein was not successful. Additionally, it has also been determined that conversions of compound 6.30 to compound 6.33, compound 6.45 to compound 6.47, and compound 6.55 to compound 6.66 therein were also not successful as reported therein. The source of the failure has been traced to the instability of intermediate tetraepoxide species (e.g. compounds 6.28, 6.30, 6.45, and 6.55 therein) thought to have been observed in the reaction mixtures.
In spite of the above reports, there is currently a need for novel intermediates and methods that can be used to synthesize complex cyclic compounds such as macrolides. There is also a need for novel macrolide compounds with useful biological properties such as antiinfective, anti-inflammatory, or antitumor properties.